Related Serious Adverse Events Research Articles

Efficacy and safety of a single-use cholangioscope for percutaneous transhepatic cholangioscopy.

Background and study aims Percutaneous transhepatic cholangioscopy (PTCS) is a management option for patients in whom peroral cholangioscopy or endoscopic retrograde cholangiopancreatography (ERCP) fail. We conducted a case series on the efficacy and safety of PTCS using a cholangiopancreatoscope cleared by the US Food and Drug Administration in 2020. Patients and methods Fifty adult patients scheduled for PTCS or other cholangioscopic procedure were enrolled at seven academic medical centers and followed for 30 days after the index procedure. The primary efficacy endpoint was achievement of clinical intent by 30 days after the index PTCS procedure. Secondary endpoints included technical success, procedure time, endoscopist ratings of device attributes on a scale of 1 to 10 (best), and serious adverse events (SAEs) related to the device or procedure. Results Patients had a mean age of 64.7±15.9 years, and 60.0% (30/50) were male. Forty-four patients (88.0%) achieved clinical intent by 30 days post-procedure. The most common reasons for the percutaneous approach were past (38.0%) or anticipated (30.0%) failed ERCP. The technical success rate was 96.0% (48/50), with a mean procedure time of 37.6 minutes (SD, 25.1; range 5.0-125.0). The endoscopist rated the overall ability of the cholangioscope to complete the procedure as a mean 9.2 (SD, 1.6; range 1.0-10.0). Two patients (4.0%) experienced related SAEs, one of whom had a fatal periprocedure aspiration. Conclusions PTCS is an important endoscopic option for selected patients with impossible retrograde access or in whom ERCP fails. Because of the associated risk, this technique should be practiced by highly trained endoscopists at high-volume centers. (ClinicalTrials.gov number, NCT04580940).

Long-Term Clinical Safety of the Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: A Prospective, Multi-Country, Observational Study.

In this prospective, observational study (ClinicalTrials.gov Identifier: NCT02661464), long-term safety information was collected from participants previously exposed to the Ebola vaccines Ad26.ZEBOV and/or MVA-BN-Filo while enrolled in phase 1, 2, or 3 clinical studies. The study was conducted at 15 sites in seven countries (Burkina Faso, France, Kenya, Tanzania, Uganda, the United Kingdom, and the United States). Adult participants and offspring from vaccinated female participants who became pregnant (estimated conception ≤28 days after vaccination with MVA-BN-Filo or ≤3 months after vaccination with Ad26.ZEBOV) were enrolled. Adults were followed for 60 months after their first vaccination, and children born to female participants were followed for 60 months after birth. In the full analysis set (n = 614 adults; median age [range]: 32.0 [18-65] years), 49 (8.0%) had ≥1 serious adverse event (SAE); the incidence rate of any SAE was 27.4 per 1000 person-years (95% confidence interval: 21.0, 35.2). The unrelated SAEs of malaria were reported in the two infants in the full analysis set, aged 11 and 18 months; both episodes were resolved. No deaths or life-threatening SAEs occurred during the study. Overall, no major safety issues were identified; one related SAE was reported. These findings support the long-term clinical safety of the Ad26.ZEBOV and MVA-BN-Filo vaccines.

Safety and Efficacy of Relmacabtagene Autoleucel (relma-cel) in Adults with Relapsed/Refractory Mantle Cell Lymphoma (r/r MCL): Updated Results from a Phase II Open-Label Study in China

Background: Mantle cell lymphoma (MCL), an aggressive subtype of B-cell non-Hodgkin lymphoma, predominantly affects elderly males. Poor overall response rates (ORR) and high rates of recurrence are observed for those patients after discontinuation or failure from Bruton 's tyrosine kinase inhibitors (BTKi), with median overall survival (OS) of 6~10 months. A phase II open label study (NCT04718883) for relma-cel reported the first efficacy and safety data in 11 Chinese patients with relapsed/refractory Mantle Cell Lymphoma (r/r MCL) in ASH 2022. This abstract provides the updated data based upon 56 patients. The study is still ongoing. Methods: The study enrolled patients with confirmed diagnosis of MCL, relapsed or refractory after at least 2 lines of prior therapies including anti-CD20 antibody, anthracycline or bendamustine, andBTKi. After lymphodepleting chemotherapy, patients received relma-cel (100×10 6 CAR+ Tcells). Bridging therapy was allowed. Primary endpoint was ORR at month 3 assessed by investigator, and secondary endpoints included complete response rate (CRR) at month 3, duration of response (DoR), progression-free survival (PFS), OS, pharmacokinetics (PK), pharmacodynamics (PD) and safety. Results: As of June 30, 2023, 66 patients enrolled and receivedleukapheresis. Relma-cel was administered in 56 patients (78.6% males; median age of 59.5 years). 42 patients had tumor assessment at month 3 or discontinued treatment due to death, disease progression before evaluation. The study population had poor prognostic factors at baseline: Age: 19 (33.9%) ≥ 65 years oldPathology: 13 (23.2%) with blastoid and 6 (10.7%) with pleomorphic variants30 (53.6%) with extranodal lesions, 4 (7.1%) with gastrointestinal involvement; 28 (50.0%) with spleen involvement, 17 (30.4%) with bone marrow involvementMCL International Prognostic Index (MIPI) score ≥ 4: 27 (48.2%)High tumor burden: 17 (30.4%) had bulky disease ≥ 5 cm Over 65% patients received ≥ 3 lines of prior therapies, including 25.0% patients received ≥ 5 lines. Almost all patients failed to BTKi (29 [51.8%] relapsed and 25 [44.6%] refractory). Seven (12.5%) patients relapsed after hematopoietic stem cell transplantation (HSCT). Twenty-six (46.4%) patients underwent bridging therapy. At month 3, of the 42 efficacy-assessable patients, 27 (64.29%) reached objective responses (OR), and 23 (54. 76%) achieved complete response (CR). Best ORR was 78.57% and best CRR was 66.67%. Based on the safety analysis set of 56 patients, 52 (92.86%) patients had treatment emergent adverse events (TEAE), including 44 (78.57%) with treatment related TEAE of grade ≥ 3. Twenty-five (44.64%) patients had serious adverse events (SAE), and 13 (23.21%) with treatment related SAE. Thirty-one (55.36%) patients had cytokine release syndrome (CRS), 3 (5.36%) with grade ≥ 3. Six (10.71%) patients had neurotoxicities (NT), 4 (7.14%) with grade ≥ 3. Twenty-seven (48.21%) patients had infections, 15 (26.79%) with grade ≥ 3. Forty-seven (83.93%) patients had prolonged cytopenia, 38 (67.86%) with grade ≥ 3. Eighteen (32.1%) deaths occurred, 6 (10.7%) died from disease progression, 8 (14.3%) due to AE, 2 (3.6%) died from treatment related AE, 4 (7.2%) from other reasons or unknown causes. Conclusions: In this phase II study, relma-cel continually demonstrated high response rates (best ORR: 78.57%; best CRR: 66.67%) and good tolerability in patients with r/r MCL.

1363. Preliminary Safety Results from a Phase 1 First in Human Study of VYD222: an Extended Half-Life Monoclonal Antibody (mAb) in Development for COVID-19 Prevention

Abstract Background VYD222 is a fully human IgG1 mAb demonstrating broad and potent in vitro neutralizing activity across SARS-CoV-2 variants including XBB.1.5. VYD222 is a re-engineered version of adintrevimab, an Fc-modified mAb that has a robust safety data package and demonstrated clinically meaningful results in Phase 2/3 clinical trials for both treatment and prevention of COVID-19 (NCT04805671, NCT04859517). VYD222 is currently in development for COVID-19 prevention. Methods This is an ongoing Phase 1, first in human, blinded, randomized, placebo (PBO)-controlled, single ascending dose study of VYD222 administered as slow intravenous (IV) push to healthy adults aged 18-65 years (NCT05791318). Participants were randomized 8:2 in each of 3 cohorts (n=8 VYD222, n=2 PBO): VYD222 1500 mg, 2500 mg, and 4500 mg. Safety and tolerability will be assessed as incidence of treatment emergent adverse events, including serious adverse events (SAEs). Serum pharmacokinetic (PK) parameters will be calculated for VYD222 using noncompartmental analysis methods. Serum virus neutralizing antibody (sVNA) titers of VYD222 ex vivo against relevant SARS-CoV-2 variants will be assessed using a validated assay. Safety, tolerability, PK, and sVNA titers will be assessed through 12 months post-dose. Here we report preliminary blinded safety results from cohorts 1 and 2. Results Overall, 12 participants received VYD222 or PBO. Through a minimum of 14 days post dose, among 10 participants in cohort 1 (VYD222 1500 mg n=8, PBO n=2), there were 9 AEs (adverse events) reported, all of which were mild in severity and considered unrelated to study drug. No participant experienced SAEs, infusion-related reactions, or hypersensitivity reactions. Through 2 days post dose, 2 sentinel participants in cohort 2 (VYD222 2500 mg n=1, PBO n=1) experienced zero AEs, study drug related AEs, SAEs, infusion-related reactions, or hypersensitivity reactions. Enrollment continues in cohort 2 as of the data cutoff (04/25/2023) for this abstract. Data remain blinded currently. Conclusion To date, a single dose of VYD222, up to 2500 mg IV push, was well tolerated across all healthy participants receiving either VYD222 or PBO in this ongoing phase 1 study. These findings support continued clinical development of VYD222. Disclosures Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Natalia Betancourt, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Aanika Das, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Ed Campanaro, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds Pete Schmidt, MD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds

Apoptotic cells for treatment of acute respiratory distress syndrome associated with COVID-19.

Hyper-inflammatory immune response, a hallmark of severe COVID-19, is associated with increased mortality. Acute respiratory distress syndrome (ARDS) is a common manifestation. We undertook two phase I/II studies in five and then 16 subjects with severe/critical COVID-19 to assess the safety and preliminary efficacy of apoptotic cells (Allocetra™-OTS, Enlivex Therapeutics), a cellular immunomodulatory therapy that reprograms macrophages to reduce hyper-inflammatory response severity. Eligible patients presenting to the Emergency Room with severe COVID-19 and respiratory dysfunction received one intravenous administration of Allocetra™-OTS and were monitored for adverse events (AEs) for 28 days. The primary aim was to determine the safety profile of treatment; secondary aims were recovery from ARDS, intensive care unit (ICU) and hospital length-of-stay, and mortality. Immune modulator markers were measured to elucidate the mechanism of action of Allocetra™-OTS. 21 patients with severe-critical COVID-19 of Gamma, Alpha and Delta variants, were treated with a single dose of apoptotic cells. 19/21 patients had mild-to-severe ARDS at presentation. Median age was 53 years, 16/21 were males, 16/21 were overweight/obese. No serious related adverse events (SAEs) were reported. All 21 study subjects survived to day 28 (end of study); 19/21 recovered completely. Comparable mortality rates at the hospital were 3.8%-8.9% for age- and gender-matched patients, and 39%-55% for critical patients. Recovering patients exhibited rapid ARDS resolution and parallel resolution of inflammation markers and elevated cytokines/chemokines. In patients with severe/critical COVID-19 associated with ARDS, Allocetra™-OTS was safe, well-tolerated, and showed promising results for resolution of respiratory failure and inflammation. https://clinicaltrials.gov/ct2/show/study/NCT04513470, https://clinicaltrials.gov/ct2/show/study/NCT04590053, Identifiers NCT04513470, NCT04590053.

15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .

Real-world Safety and Effectiveness of 24-week Sofosbuvir and Ribavirin Treatment in Patients Infected with Rare Chronic Hepatitis C Virus Genotypes 3, 4, 5, or 6 in Japan.

Objectives Real-world evidence on the safety and effectiveness of direct-acting antivirals in patients infected with chronic hepatitis C virus (HCV) genotypes (GTs) 3, 4, 5, or 6 in Japan is limited. This prospective observational study assesses the real-world safety profile and treatment effectiveness among patients prescribed sofosbuvir with ribavirin (SOF+RBV) for HCV GT3-6 infection in Japan. Methods Adults receiving 24-week SOF+RBV treatment for HCV GT3-6 infection were prospectively enrolled and observed through 24 weeks post-treatment for treatment-emergent adverse events (AEs) considered related to SOF and/or RBV by treating physicians and for a sustained virologic response at 12 and 24 weeks post-treatment (SVR12, SVR24). Incidence rates of related AEs and serious AEs (SAEs) were calculated. Proportions of patients experiencing related AEs/SAEs and those achieving SVR12 and SVR24 were assessed overall and by baseline characteristics, including treatment experience and cirrhosis status. Results Among the 50 patients included in the safety analysis, 92% had GT3 infection. The incidence rates of related AEs and SAEs were low overall (1.52 and 0.25 per 100 person-weeks, respectively), with 6.0% and 14.0% patients experiencing AEs related to SOF or RBV, respectively. There were no marked differences in the occurrence of related AEs/SAEs by patient baseline characteristics. SVR12 and SVR24 were achieved in 83.7% (41/49) and 82.2% (37/45) of patients, respectively. Lower effectiveness was observed among treatment-experienced patients and patients with cirrhosis at baseline. Conclusions This study demonstrated that SOF+RBV treatment for HCV GT3-6 infection was safe, effective, and an important treatment option for this difficult-to-treat patient population in Japan.

LBA01-05 PIVOTAL STUDY OF A NOVEL WIRELESSLY POWERED, PATIENT TAILORED PROGRAMMED, TIBIAL NEUROSTIMULATOR FOR THE TREATMENT OF PATIENTS WITH OVERACTIVE BLADDER

You have accessJournal of UrologyCME1 Apr 2023LBA01-05 PIVOTAL STUDY OF A NOVEL WIRELESSLY POWERED, PATIENT TAILORED PROGRAMMED, TIBIAL NEUROSTIMULATOR FOR THE TREATMENT OF PATIENTS WITH OVERACTIVE BLADDER John Heesakkers, Alessandro Digesu, Suzette Sutherland, Osvaldo Padron, Cindy Amundsen, Rebecca McCrery, Emily Kean, Kevin Benson, Kevin Cline, Kaiser Robertson, Felicia Lane, Frank Martens, Stefan De Wachter, Kimberley Ferrante, Laura Giusto, Roger Dmochowski, and Philip Toozs-Hobson John HeesakkersJohn Heesakkers More articles by this author , Alessandro DigesuAlessandro Digesu More articles by this author , Suzette SutherlandSuzette Sutherland More articles by this author , Osvaldo PadronOsvaldo Padron More articles by this author , Cindy AmundsenCindy Amundsen More articles by this author , Rebecca McCreryRebecca McCrery More articles by this author , Emily KeanEmily Kean More articles by this author , Kevin BensonKevin Benson More articles by this author , Kevin ClineKevin Cline More articles by this author , Kaiser RobertsonKaiser Robertson More articles by this author , Felicia LaneFelicia Lane More articles by this author , Frank MartensFrank Martens More articles by this author , Stefan De WachterStefan De Wachter More articles by this author , Kimberley FerranteKimberley Ferrante More articles by this author , Laura GiustoLaura Giusto More articles by this author , Roger DmochowskiRoger Dmochowski More articles by this author , and Philip Toozs-HobsonPhilip Toozs-Hobson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003360.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The BlueWind Medical Device is a novel miniature, leadless, battery-less, sub-facially implantable tibial neuromodulation system. The implant is wirelessly powered and modulated by an external wearable unit. A Clinician Programmer is used to individually tailor stimulation parameters (i.e., frequency, pulse width and amplitude). A pivotal trial was conducted to evaluate the safety and efficacy of the BlueWind Medical Device for treating Urge Urinary Incontinence (UUI) in women. METHODS: One hundred and fifty-one women with UUI were enrolled in 23 centers in the United States and Europe, for this prospective, single arm, open-label study. Inclusion criteria required at least 9 UUI episodes during a 7-day diary. The device was activated ∼4 weeks after implantation, and the patients performed daily stimulation treatments at home for ∼30 minutes twice daily. Stimulation parameters were individually tailored according to a predefined algorithm per patient sensation and response. Multiple Treatment Programs were provided for patients when needed. Voiding diaries, quality of life and patient satisfaction questionnaires were collected at 6 and 12 months after device activation. The primary safety measure was incidence of Adverse Events (AE) at 12 months post activation. Primary efficacy end point was defined as ≥50% reduction in UUI episodes compared to baseline. RESULTS: One hundred and fifty-one subjects, mean age 58.8 (SD: 12.5) were implanted. The subjects demonstrated mean baseline of 4.8 UUI/day (SD 2.9) and 10 voids/day (SD 3.3). Results are presented based on the intend to treat analysis set with 144 and 140 patients reaching 6- and 12-months post activation, respectively. No device or procedure related Serious Adverse Events (SAE) were reported by 12 months. At 6 and 12 months, 76.4% and 78.4% of the subjects were therapy responders (p<.0001), respectively, with 50% of the subjects dry at 12 months (on 3 consecutive days diary). At 12 months, 84.6% of the patients showed ≥10 points improvement (Minimal Important Difference; MID) in Health Related Quality of Life (p<.0001). CONCLUSIONS: The BlueWind Medical Device has demonstrated an excellent safety profile with no device or procedure related SAEs. Efficacy endpoints were met with high proportion of dry patients, high compliance, and high patient satisfaction. Source of Funding: BlueWind Medical is the Sponsor of OASIS trial © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1178 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Heesakkers More articles by this author Alessandro Digesu More articles by this author Suzette Sutherland More articles by this author Osvaldo Padron More articles by this author Cindy Amundsen More articles by this author Rebecca McCrery More articles by this author Emily Kean More articles by this author Kevin Benson More articles by this author Kevin Cline More articles by this author Kaiser Robertson More articles by this author Felicia Lane More articles by this author Frank Martens More articles by this author Stefan De Wachter More articles by this author Kimberley Ferrante More articles by this author Laura Giusto More articles by this author Roger Dmochowski More articles by this author Philip Toozs-Hobson More articles by this author Expand All Advertisement PDF downloadLoading ...

Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study

NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine ismanufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using anEnzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort byELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. SIIPL, Indian Council of Medical Research, Novavax.

Preliminary Safety and Efficacy of Relmacabtagene Autoleucel (relma-cel) in Adults with Relapsed/Refractory Mantle Cell Lymphoma (r/r MCL) in China

Background: MCL is an aggressive subtype of B-cell non-Hodgkin lymphoma with median overall survival (OS) of approximately 3-4 years from diagnosis. However, OS is even shorter (6~10 months) after discontinuation or failure from Bruton's tyrosine kinase inhibitors (BTKi) and these patients have poor overall response rates (ORR) and high rates of recurrence. Relma-cel is a CD19 directed CAR-T product, and here we report the first results of relma-cel from a phase II single arm study (NCT04718883) in adults with r/r MCL. Methods: Patients with confirmed MCL, relapsed or refractory after at least 2 lines of therapy including anti-CD20 antibody, anthracycline or bendamustine, and BTKi were enrolled. After lymphodepleting chemotherapy, participants received relma-cel (100×106 CAR+ Tcells). Bridging therapy was allowed. Primary endpoint was ORR at month 3, and secondary endpoints included complete response rate (CRR) at month 3, duration of response (DoR), progression-free survival (PFS), OS, pharmacokinetics (PK), pharmacodynamics (PD) and safety. Results: As of Nov 30, 2021, 35 participants were enrolled. Relma-cel was manufactured for 24 participants and administered to 18. A total of 11 participants completed 3 months follow-up. Based on the analyses set of the 11 participants, the median age was 57 years old (min-max: 46-72), and 9 participants (81.8%) were male. Many had poor prognostic factors at baseline, including 5 (45.5%) age >65 years, organ involvement [5 bone marrow, 3 spleen, 1 lung, 1 gastrointestinal tract], 6 (54.5%) had Mantle-Cell Lymphoma International Prognostic Index (MIPI) score >3, and 5 had blastoid and 1 pleomorphic variants. High tumor burden was observed in 2 (sum of the products of diameters [SPD] of 14,251 and 19,124 mm2). Participants received up to 7 lines of prior therapies (9/11 [81.8%] ≥ 3 lines; 4/11 [36.4%] ≥ 5 lines), and 9/11 (81.8%) had progressed after the last line. All 11 participants received and failed BTKi, and the median line of BTKi-based therapy was 3. Three participants (27.3%) underwent bridging therapy, Platinum or Cytarabine or combination (Table 1). Of the 11 efficacy assessable participants, 8 participants had partial response (PR) or complete response (CR) (ORR 72.7%) and 6 achieved CR (CRR 54.5%) at month 3 landmark evaluation. Best ORR was 81.8% and best CRR was 54.5%. All 11 participants had treatment emergent adverse event (TEAE), which were assessed by investigator as treatment related TEAE, including 9 participants with treatment related TEAE of grade ≥3. Five participants had serious adverse event (SAE), and 2 of them experienced relma-cel related SAE. Six participants (54.5%) had cytokine release syndrome (CRS), including 1 grade ≥3. Two participants had immune effector cell-associated neurotoxicity syndrome (ICANS), including 1 grade ≥3. Two deaths occurred. One died after disease progression, and the other died from pulmonary infection. Safety data and PK parameters are shown in the Table 2. Conclusions: In this phase II study in China, the preliminary data of relma-cel provided promising clinical efficacy outcome (best ORR 81.8%, best CRR 54.5%) in high risk patients with r/r MCL and a low incidence of grade ≥3 CRS and ICANS. This study is ongoing and further results will be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First in Human (FIH) Study of GFH009, a Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, in Patients with Relapsed/Refractory (r/r) Hematologic Malignancies

Background: The key roles of cyclin-dependent kinases in cell proliferation and various aspects of transcription have led to efforts to develop CDK inhibitors as cancer therapeutics. Positive transcription elongation factor b (PTEFb) consisting of Cyclin T and CDK9 is a key regulator of transcription in cancer cells. It is vital for transcription of short-lived gene products, such as MYC and MCL-1, that maintain cancer cell survival. GFH009 is a potent and highly selective CDK9 inhibitor. Here we report preliminary safety and efficacy data from the FIH study of GFH009 in patients with r/r hematologic malignancies (NCT04588922). Methods: This is a phase I, multicenter, dose-escalation trial of GFH009 enrolling patients with relapsed/refractory acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) or lymphoma. The Bayesian optimal interval (BOIN) design is employed in the dose escalation cohorts of 3-6 patients. In the first part of the trial, GFH009 was administered intravenously over 30-60 minutes twice per week. The primary endpoint was to evaluate the safety of GFH009 measured by adverse events using common terminology criteria for adverse event (CTCAE) v5.0 and dose limiting toxicities (DLTs). Disease responses were evaluated using Lugano (2014) for lymphoma, IWG criteria (2003) for AML, and iwCLL (2018) for CLL/SLL. Blood samples were collected and analyzed for pharmacokinetics (PK) and pharmacodynamics (PD). Results: As of 15 July 2022, a total of 46 patients were screened, and 30 received at least one dose of GFH009 as monotherapy, including 16 lymphoma patients in 2.5, 4.5, 9 and 15 mg dose cohorts and 14 AML patients in 9, 15, 22.5 and 30 mg dose cohorts. The median age was 52 (range 18-73), and 53% were male. Nine patients (30%) discontinued treatment due to disease progression, eight (27%) due to subjects’ decision and six (20%) due to lack of efficacy. No DLTs were observed to date. The most common drug related AEs were white blood cell decreased [20.0% (6/30), 6.7% (2/30) of which was ≥ G3], neutrophil count decreased [16.7% (5/30), 6.7% (2/30) ≥ G3] and anemia [13.3% (4/30), 3.3% (1/30) ≥ G3]. G3/G4 treatment emergent AEs recorded in >10% of patients included anemia, white blood cell decreased, platelet count decreased, neutrophil count decreased and pneumonia. The total of 12 serious adverse events (SAEs) occurred in 11 subjects, three of which were drug related. All the drug related SAEs were G3 pneumonia. One death was recorded due to disease progression of AML. Four lymphoma patients (3 in 4.5 mg and 1 in 9 mg) achieved stable disease (SD) including one peripheral T cell lymphoma (PTCL), one diffuse large B-cell lymphoma, one Hodgkin lymphoma and one mucosa-associated lymphoid tissue (MALT) lymphoma. The patient with PTCL at 9 mg dose had 62% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) based on computed tomography (CT). The duration of treatment of the PTCL patient and MALT lymphoma patient was 12 weeks and 41 weeks respectively and they continue treatment at the cut-off date. No objective response was observed in AML patients, but two patients, one at 9 mg dose level and one at 15 mg dose level, had decrease of bone marrow blasts ≥ 50%. PK exposure increased in a dose-proportional manner as increasing dose from 2.5 mg to 22.5 mg. The mean half-life ranged from 14.9 h to 17.7 h. Pharmacodynamic assessment of MYC and MCL1 mRNA in whole blood showed post-dose reduction of short half-life mRNA transcripts at higher dose levels. Conclusion: GFH009 as monotherapy is well tolerated at the tested doses and has shown clinical activity in patients with r/r lymphoma. The dose escalation in patients with AML and lymphoma is ongoing. Different dosing regimens are currently being explored for potentially better inhibition on the target. GFH009 add-back in patients refractory to or relapsed while on venetoclax and hypomethylating agents is planned in AML patients. Key words: cyclin-dependent kinases, CDK9 inhibitor, MYC, MCL-1, AML, lymphoma, CLL, SLL, PTCL, MALT lymphoma

O.06 Long term outcomes for X-Linked myotubular Myopathy (XLMTM) with gene replacement therapy, resamirigene bilparvovec: Preliminary results from ASPIRO

ASPIRO (NCT03199469) is a first-in-human clinical study of resamirigene bilparvovec (AT132), an AAV-mediated, muscle-directed gene replacement therapy in boys with ventilator-dependent XLMTM, a devastating congenital myopathy. We previously reported study outcomes through 48 weeks following dosing, including 4 participants with treatment-related, fatal, hepatobiliary toxicity. Here we report long-term outcomes among the 20 surviving dosed participants (new data cut of 01MAR2022): n=6 at 1.3 x 1014 vg/kg AT132, (dosing age, median 0.9 [range, 0.8–4.1] years; post-dose follow-up period age, 4.1 [3.9–4.4] years); n=14 at 3.5 x 1014 vg/kg AT132 (dosing age, 1.9 [0.6–6.0] years; post-dose follow-up period, 2.5 [1.9–5.6] years). All participants were ventilator dependent at baseline (mean: 22.8 hours/day). Currently, 6/6 lower- and 10/14 higher-dosed participants are ventilator independent, and 4/6 lower-, and 5/14 higher-dosed patients have been decannulated. At baseline, 1/6 lower-dose and none of higher-dose participants were able to sit independently; none had achieved more advanced milestones. At data cut, all participants have achieved major motor milestones: 5/6 lower-and 4/14 higher-dose participants achieved and maintained independent walking (achieved mean 38.8 [SD, 14.1] months); 4/6 lower-and 2/14 higher-dose participants have achieved the ability to ascend stairs. Among the surviving participants, 2/6 lower- and 7/14 higher-dose experienced treatment-related serious adverse events (SAEs); 5/20 had hepatobiliary related SAEs. Overall, significant improvements and maintenance of ventilator independence, respiratory muscle strength and skeletal muscle function were observed compared to untreated controls. These substantial long-term durable improvements must be weighed against the occurrences of fatal serious adverse events, for which the ASPIRO program is on clinical hold while relevant clinical information is being gathered and reviewed.

Efficacy and Safety of Tisotumab Vedotin in Patients with Head and Neck Squamous Cell Carcinoma: Results From a Phase II Cohort

<h3>Purpose/Objective(s)</h3> Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. <h3>Materials/Methods</h3> In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. <h3>Results</h3> Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. <h3>Conclusion</h3> TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209).

Abstract P2-13-45: Interim results of a phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors

Abstract Background: Engineered toxin bodies (ETBs) are composed of a de-immunized Shiga-like Toxin A subunit genetically fused to an antibody-like binding domain. ETBs can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other therapeutics. MT-5111 is a 55 kD ETB targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adult pts with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics (PK), efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study enrolls pts with HER2+ tumors into 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg/dose. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and other HER2+ tumors. All pts receive MT-5111 weekly as 30-min IV infusions in each 21-day treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: Per data cut in June 2021, 21 pts (mean age 64 years, range 34-78; 38% male) in cohorts 1-6 with breast (n=7), biliary (n=6), gastric (n=3), pancreatic (n=2), lung (n=2), and colon (n=1) cancer were treated (Table 1). Pts had a median of 4 prior lines of systemic therapies (range, 1-8) and 2 prior lines of HER2-targeting treatments (range, 0-6). No Grade (G)4 or 5 tx-emergent (TE) adverse events (AEs) occurred. Tx-related AEs occurred in 11 (52%) pts; the most common was fatigue (n=7, 33%). One pt (4.5 µg/kg) had a possibly (per PI) related G3 serious AE (SAE) of dyspnea and hypoxia, but also lymphangitic carcinomatosis and H. influenzae infection. The other related SAE occurred in a pt (6.75 µg/kg) who had a G1 transient troponin increase without concomitant cardiac symptoms or ECG/ECHO changes. All other related AEs were ≤G2. There were no clinically significant changes in cardiac biomarkers (troponin, ECG, left ventricular ejection fraction) nor were there cases of capillary leak syndrome. Two pts (3 µg/kg and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies, and Cmax data at 6.75 µg/kg indicated that current in-human exposure was between the IC50 values of high and medium HER2-expressing cell lines (approximately 10-89 ng/mL). Thus, a dose of at least 10 µg/kg may be required to achieve effective exposure. To date, no dose-limiting toxicities have been observed and the 10 µg/kg/dose cohort is now accruing. Conclusions: MT-5111 was well tolerated with no clinically significant immuno- or cardiotoxicity. Dose escalation is ongoing and nearing levels expected to be required for efficacious exposure. Table 1.Metastatic HER2 status and MT-5111 treatment by cohortDose0.5 µg/kg1.0 µg/kg2.0 µg/kg3.0 µg/kg4.5 µg/kg6.75 µg/kgCohort123456Number of patients treated with MT-5111433335Metastatic HER2 2+ by IHC: ALL/BC1/11/11/01/10/04/0Metastatic HER2 3+ by IHC: ALL/BC3/12/02/12/13/01/1BC, breast cancer. Citation Format: Brian A. Van Tine, Monica Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Angela Georgy, Joshua Pelham, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Zev A. Wainberg. Interim results of a phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-45.

A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors: Interim results.

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

Safety and Preliminary GvHD Mitigation in First in Human Clinical Trial of Apograft in Match Related Stem Cell Transplantation (SCT)

Graft versus host disease (GvHD) is a major frequent adverse event (AE) and the primary cause of morbidity and mortality following allogeneic stem cell transplantation (ASCT).Numerous attempts to reduce incidence and severity of GvHD using a variety of cell selection methods have been employed, but they all suffer from a risk/benefit trade-off where reduction of GvHD-causing cells leads to reduced engraftment and/or reduced graft vs. tumor (GvT) effect.We have previously reported development of a new method for cell selection, which take advantage of cells' differential sensitivity to CD95 receptor mediated apoptosis. This technology enables the differential selection of transplant related immune-toxicity cells (e.g., TH1, TH17, terminally differentiated B cells and antigen presenting cells {APCs}) while maintaining stem and progenitor cells. Thus, selecting the right mix of cells may enable both GvHD reduction and maintenance of the graft's effectiveness.Here we report results of our first in humans clinical trial using this functional cell selection technology (named ApoGraft). This study was an Open-Label Phase 1/2 Pilot, Staggered Four-Cohort Safety and Proof-of-Concept Study of ApoGraft in the Prevention of Acute Graft Versus Host Disease in Match related SCT (NCT02828878). The primary objective of the trial was to demonstrate safety and tolerability of ApoGraft in adult patients with hemato-oncology disorders. The key secondary objective was engraftment and prevention of acute GvHD.Eleven patients were enrolled into this study in 4 sequential cohorts of 3 patients each, except for 2 patients in cohort 4. Enrolled subjects' transplant indications included AML (n=7), ALL (n=1), MDS (n=2) and biphenotypic acute leukemia (n=1). ApoGraft was manufactured ex-vivo from donor mobilized peripheral blood cells (MPBCs) collected via a single apheresis donation that was incubated for 2 hours with FasL protein (10, 25, 50 and 100 ng/ml per cohort), and washed before transplantation to the recipient. Patients were administered with a single ApoGraft treatment. The ApoGraft product median CD34+ yield was 72%, with a median of 4.3x10^6 CD34+ cells/Kg/patient. All patients received GVHD prophylaxis with short-course methotrexate and Cyclosporin A.No AEs or serious AEs (SAEs) were recorded during stem cell infusion. Six months follow-up showed ApoGraft transplantation to be well tolerated with no related AEs or SAEs. Successful engraftment was observed in all subjects within the expected timeframe. Median time to neutrophils or platelets engraftment was 14 days. Lower incidence of grade 2-4 aGvHD was observed in Cohorts 3 and 4 (n=2) as compared to Cohorts 1 and 2 (n=5). None of the higher FasL dose Cohort 3 and Cohort 4 patients had grade 3 and 4 aGvHD compared to 3 patients in cohorts 1 and 2. Over 97% of bone marrow at 28 days post-transplant were of donor origin, indicating full donor chimerism, except for the two MDS patients; one had shown full donor chimerism, which was reduced at day 180 (55%). The other had a donor chimerism of 92% at day 28. None of the patients relapsed during the study period. Four of 6 patients in the 10 and 25 ng/ml cohorts had 7 episodes of CMV viremia, as compared with 1 episode in the 50ng/ml cohort and none in the 100ng/ml cohort. Ten patients survived and were progression-free by study day 180. One MDS patient died during the study due to study unrelated secondary graft failure.Our results show evidence that the ApoGraft product was well tolerated at all FasL doses and demonstrated preliminary signs of GvHD mitigation when the higher ex-vivo doses of FasL (50 and 100 ng/ml) were used. DisclosuresZuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Kamar: Cellect Biotheraputics: Consultancy.

An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

Background and ObjectivesTo report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations.MethodsPD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg.ResultsNo serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector–related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%–30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III “off”-medication and “on”-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.DiscussionsVY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Trial Registration InformationNCT01973543.Classification of EvidenceThis study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Safety and Efficacy Of Ferumoxytol For The Episodic Treatment Of Iron Deficiency Anemia In Patients With a History Of Unsatisfactory Oral Iron Therapy: Results Of a Phase III Open-Label, Six Month Extension Study

▪ BackgroundThe efficacy of intravenous iron replacement in treating iron deficiency anemia (IDA) has been studied in patients with various underlying conditions. In some conditions like abnormal uterine and gastrointestinal bleeding, there may be ongoing blood loss leading to a continuing need for treatment that may require episodic iron replacement. MethodsA 6 month Phase III, open-label extension study was designed to evaluate the safety and efficacy of ferumoxytol (FER) for the episodic treatment of IDA patients with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. The study enrolled patients from a double-blind, placebo (P)-controlled 5-week Phase III study, who had been randomized 3:1 to treatment with FER or P and completed that study. Enrolled patients were evaluated for IDA monthly throughout the 6-month Observation Period. Those with persistent or recurrent IDA (defined as Hgb <11.0 g/dL and TSAT <20%) at any evaluation visit, began a 5-week Treatment Period (TP), receiving a course of FER (2 x 510 mg) with response assessed at TP Week 5. ResultsThis extension study enrolled 78.5% of patients from the previous Phase III study (163/200 P, 471/608 FER), of whom 93% of the P- and 39% of the FER-treated patients met treatment criteria during the 6-month extension and received at least 1 course of FER. In the remaining (12 P, 285 FER) patients, mean monthly Hgb remained ≥12.1 g/dL without further treatment. Mean Hgb increased significantly (p<0.0001) from TP Baseline to TP Week 5 following Treatment Course 1 (2.6 g/dL; N=151) and repeat courses (Course 2: 1.5 g/dL, N=244 [38.5%]; Course 3: 1.1 g/dL, N=69 [10.9%]); mean Week 5 Hgb was comparable following Courses 1, 2 and 3. The few patients receiving Treatment Courses 4 (N=18) or 5 (N=4) limited further analyses. Overall, 61% of FER treated patients never required a 2nd course of treatment. Statistically significant (p<0.0001) increases in mean TSAT from TP Baseline to TP Week 5 followed Course 1 and subsequent courses.FER was also well-tolerated and no new safety signals were observed among patients who received repeat dosing. The incidence of treatment emergent adverse events (TEAEs) was 47.7%, 38.1% and 37.7% in patients who received Course 1, 2 and 3 of FER, respectively. The pattern of related TEAEs decreased in subsequent courses, and none were reported in patients who received more than 3 courses. The incidence of serious adverse events (SAEs) was comparable in patients who received Course 1, 2 and 3, and most were attributable to comorbidities and/or procedural complications; no related SAEs or deaths were reported. For all other TEAE categories, no clear pattern of incidence was observed between Treatment Courses. [Display omitted] ConclusionFER (2x 510 mg) delivered over multiple treatment courses was generally well tolerated in IDA patients with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used with persistent or recurrent IDA; Week 5 post-treatment Hgb was comparable following Courses 1, 2 and 3. No trend of increasing incidence of TEAEs was identified with repeat dosing, and a consistent, positive and robust treatment effect was observed. Durability of the treatment effect following FER was demonstrated by the majority of patients not requiring further iron treatment following the initial course during this 6 month extension study. Disclosures:Vadhan-Raj:AMAG Pharmaceuticals, Inc: Research Funding. Off Label Use: Feraheme (ferumoxytol) injection. For treatment of iron deficiency anemia in non-CKD patients. Dahl:AMAG Pharmaceuticals, Inc: Employment. Lau:AMAG Pharmaceuticals, Inc: Employment. Bernard:AMAG Pharmaceuticals, Inc: Employment. Li:AMAG Pharmaceuticals, Inc: Employment. De:AMAG Pharmaceuticals, Inc: Employment. Allen:AMAG Pharmaceuticals, Inc: Consultancy. Strauss:AMAG Pharmaceuticals, Inc: Employment.FER Received in Extension Study (N=337) Treatment Course‡Course 1 (N=151)Course 2 (N=244)Course 3 (N=69)Efficacy Results (ITT Population)Mean Change in Hgbµ2.6 (1.6)*1.5 (1.3)*1.1 (1.3)*% Patients with Increase in Hgb ≥ 2.0 g/dL¥78.843.937.7Mean Change in TSAT (%)µ12.8 (10.2)*11.7 (12.5)*7.5 (9.1)*Safety Results (Safety Population)All AEs47.7%38.1%37.7%Related AEs12.6%5.3%2.9%SAEs4.6%4.9%4.3%Related SAEs000AEs of Special Interest- protocol-defined€00.4%0Cardiovascular AE Composite EndpointΩ1.3%0.8%1.4%AEs Resulting in Study Discontinuation2.6%04.3%Death000* p-value <0.0001 based on paired t-test‡ Course numbering based on treatment received in placebo-controlled studyµ from Baseline to Week 5¥ at any time from Baseline to Week 5€ includes protocol defined signs and symptoms of hypotension and hypersensitivityΩ includes myocardial infarction, heart failure, moderate to severe hypertension and hospitalization due to any cardiovascular cause

Operative versus nonoperative treatment for adult symptomatic lumbar scoliosis at 5-year follow-up: durability of outcomes and impact of treatment-related serious adverse events.

Although short-term adult symptomatic lumbar scoliosis (ASLS) studies favor operative over nonoperative treatment, longer outcomes are critical for assessment of treatment durability, especially for operative treatment, because the majority of implant failures and nonunions present between 2 and 5 years after surgery. The objectives of this study were to assess the durability of treatment outcomes for operative versus nonoperative treatment of ASLS, to report the rates and types of associated serious adverse events (SAEs), and to determine the potential impact of treatment-related SAEs on outcomes. The ASLS-1 (Adult Symptomatic Lumbar Scoliosis-1) trial is an NIH-sponsored multicenter prospective study to assess operative versus nonoperative ASLS treatment. Patients were 40-80 years of age and had ASLS (Cobb angle ≥ 30° and Oswestry Disability Index [ODI] ≥ 20 or Scoliosis Research Society [SRS]-22 subscore ≤ 4.0 in the Pain, Function, and/or Self-Image domains). Patients receiving operative and nonoperative treatment were compared using as-treated analysis, and the impact of related SAEs was assessed. Primary outcome measures were ODI and SRS-22. The 286 patients with ASLS (107 with nonoperative treatment, 179 with operative treatment) had 2-year and 5-year follow-up rates of 90% (n = 256) and 74% (n = 211), respectively. At 5 years, compared with patients treated nonoperatively, those who underwent surgery had greater improvement in ODI (mean difference -15.2 [95% CI -18.7 to -11.7]) and SRS-22 subscore (mean difference 0.63 [95% CI 0.48-0.78]) (p < 0.001), with treatment effects (TEs) exceeding the minimum detectable measurement difference (MDMD) for ODI (7) and SRS-22 subscore (0.4). TEs at 5 years remained as favorable as 2-year TEs (ODI -13.9, SRS-22 0.52). For patients in the operative group, the incidence rates of treatment-related SAEs during the first 2 years and 2-5 years after surgery were 22.38 and 8.17 per 100 person-years, respectively. At 5 years, patients in the operative group who had 1 treatment-related SAE still had significantly greater improvement, with TEs (ODI -12.2, SRS-22 0.53; p < 0.001) exceeding the MDMD. Twelve patients who received surgery and who had 2 or more treatment-related SAEs had greater improvement than nonsurgically treated patients based on ODI (TE -8.34, p = 0.017) and SRS-22 (TE 0.32, p = 0.029), but the SRS-22 TE did not exceed the MDMD. The significantly greater improvement of operative versus nonoperative treatment for ASLS at 2 years was durably maintained at the 5-year follow-up. Patients in the operative cohort with a treatment-related SAE still had greater improvement than patients in the nonoperative cohort. These findings have important implications for patient counseling and future cost-effectiveness assessments.